Dental anesthetic comprising tetracaine and a vasoconstrictor for intranasal administration

ABSTRACT

The present invention relates to tetracaine based anesthetic formulations and methods of use thereof. The invention further relates to topical formulations of tetracaine and methods of topically anesthetizing body tissues. The present invention also relates to tetracaine based dental anesthetic formulations and methods for anesthetizing the maxillary dental arch using these formulations.

This application is a continuation of U.S. patent application Ser. No.15/498,986, filed Apr. 27, 2017, now pending, which is a continuation ofU.S. patent application Ser. No. 15/058,324, filed Mar. 2, 2016, nowU.S. Pat. No. 9,855,247, which is a continuation of U.S. patentapplication Ser. No. 14/027,033, filed Sep. 13, 2013, now U.S. Pat. No.9,308,191, which is a continuation of U.S. patent application Ser. No.13/262,704, filed Oct. 3, 2011, now U.S. Pat. No. 8,580,282, which is aUnited States National Stage Application under 35 U.S.C. § 371 ofInternational Application No. PCT/US2010/001002, filed Apr. 2, 2010,which claims priority to and the benefit of U.S. Provisional ApplicationNo. 61/166,680, filed Apr. 3, 2009, now expired. The entire disclosuresof each of the foregoing applications are hereby incorporated byreference herein.

TECHNICAL FIELD OF INVENTION

The present invention relates to tetracaine based anestheticformulations and methods of use thereof. The invention further relatesto topical formulations of tetracaine and methods of topicallyanesthetizing body tissues. The present invention also relates totetracaine based dental anesthetic formulations and methods foranesthetizing the maxillary dental arch using these formulations.

BACKGROUND OF THE INVENTION

The most common means for anesthetizing maxillary teeth is the use of aninfiltration injection. For example, the patient may receive a needlepenetration and injection of a local anesthetic solution at theapproximate apex of the root on the buccal surface of a tooth (or teeth)to be treated. A maxillary palatal injection of dental local anestheticcan be used for regional block anesthesia of teeth. The patient may alsoreceive a maxillary palatal injection of local anesthesia in order toeffect regional nerve blocks.

Dental anxiety, including needle or shot discomfort and phobia, is along-standing barrier to regular dental care. In a survey conducted bythe American Dental Association, 27% of the people surveyed indicated“fear of pain” as a reason to avoid dental visits. Needle injection oflocal anesthetic is recognized as the most anxiety-provoking procedurein dentistry for children and adults. Not only can the injection oflocal anesthetics produce fear, pain and an increase in blood pressure,but the increased stress of injection can result in fainting,hyperventilation, convulsions, shock, hypertension, cardiac arrest,respiratory collapse, acute allergic reaction to preservatives,bronchospasm, angina, and organ system toxicity in medically compromisedpatients. Further, local injections into target nerves can sometimeslead to permanent numbness as a result of needles damaging and/orcutting nerves. In rare cases, a severe overdose of injectableanesthetic or accidental, rapid intravascular injection of theanesthetic can even lead to death. The act of injecting is invasive(conceptually, psychologically, and physically) and is a major reasonworldwide why people avoid regular dental care and see their dentistsonly in an emergency. In fact, some studies indicate that millions ofpeople in the US are afraid of dental treatments because of pain.Without regular dental care, tooth caries, gum disease and oral cancermay be left undetected and can result in infection and serious, systemichealth issues.

In addition, the risk of exposure to bloodborne pathogens vianeedlesticks is a recognized occupational hazard in dentistry. Since1991, the Occupational Safety and Health Administration (“OSHA”) hasenforced a Bloodborne Pathogens Standard that requires employers toidentify, evaluate and implement safer medical devices to eliminate orminimize employee exposure to bloodborne pathogens. The standard wasrevised in 2001 when Congress passed the Needlestick Safety andPrevention Act. The Act set forth in greater detail employers'obligations under the Bloodborne Pathogens standard and specificallyindicated that a “safer medical device” includes needleless systems.Thus, further incentive exists to develop anesthetics that can bedelivered without the use of needles and comply with U.S. federallymandated engineered work practice controls.

Lidocaine, the most widely used local dental anesthetic today, was firstintroduced in the 1940s. Despite many attempts at developing needle-freeanesthetic, the only widely-used non-injectable, subsurface localanesthetic commercially available today is Oraqix® gel. While Oraqix®can be used in periodontal pockets during scaling or root-planingprocedures, it does not provide adequate anesthesia for use inprocedures such as filling, crowns and root canals. Further, while manyadvances in the comfort of dentistry have been made, such as behaviormodification therapy, topical numbing around the injection site, nitrousoxide, hypnosis, and TENS units, none of these advances has eliminatedthe need for needle injection.

Nasal administration of anesthetics has also been disclosed, forexample, in U.S. Pat. No. 6,413,499.

Thus, there remains a need for alternative and effective anesthetics. Inparticular, there remains a need for alternative and effectiveanesthetics and means for administering such anesthetics to a patient inorder to anesthetize the patient's teeth without creating extra oralsoft tissue numbness, discomfort, or phobia in the patient.

SUMMARY OF THE INVENTION

The present invention provides a tetracaine based anesthetic and methodsof use thereof.

In one aspect, the present invention provides a tetracaine basedanesthetic formulation which is useful for anesthetizing at least aportion of a body part, organ, or tissue.

In some embodiments, the present invention provides a nasal tetracainebased dental anesthetic formulation which is useful for anesthetizingthe maxillary dental arch. The invention is based on deliveringanesthetic to specific areas in the nasal cavity and/or nasal sinusessuch as the maxillary sinus. The invention is also based on deliveringthe anesthetic to the anterior dental plexus, extensions of the middlesuperior nerve, the posterior superior alveolar nerve, the nociceptorsof the facial and buccal nerve, and/or the sphenopalatine(pterygopalatine) ganglion.

The nerves of the upper teeth are like branches of a tree that extendthrough the nasal cavity down into the teeth. The pharmaceuticalcomposition of the present invention is administered into the rear ofthe nasal cavity, affecting the base, or “trunk,” of the nerve pathways.This anesthetizes the branches that transmit nerve impulses from all ofthe upper teeth (other than the two wisdom teeth and the second molar oneach side) as well as the A delta and C pain fibers of the facial softtissue. In some cases, the second molars are indeed anesthetized.

In one aspect, the invention provides a pharmaceutical compositioncomprising a) tetracaine, or a pharmaceutically acceptable salt thereof;b) a vasoconstrictor; and c) a pharmaceutically acceptable carrier. Inother embodiments, the pharmaceutical composition comprises a)tetracaine, or a pharmaceutically acceptable salt thereof; b) avasoconstrictor; c) a preservative; d) a viscosity enhancing agent; ande) a pharmaceutically acceptable carrier. In some embodiments, thecomposition comprises about 2.0-5.0% (w/v) tetracaine. In someembodiments, the composition comprises about 2.25-4.75% (w/v)tetracaine. In other embodiments, the composition comprises about2.5-4.0% (w/v) tetracaine. In yet other embodiments, the compositioncomprises about 2.5-3.5% (w/v) tetracaine. In other embodiments, thecomposition comprises about 3% (w/v) tetracaine. In some embodiments,the pharmaceutical composition is for intranasal administration.

The vasoconstrictors that may be included in the pharmaceuticalcompositions of the invention (including the intranasal pharmaceuticalcomposition) include, but are not limited to, indirect α₁-adrenergic;calcium channel blockers; meperidine; imidazole drugs such asoxymetazoline and xylometazoline; α₂-adrenergic agonists such asguanfacine; imidazoline (I₁) ligands; direct α₂-adrenergic agonists suchas clonidine; substance P blockers/reducers such as capsaicin;I-menthol; icilin; epinephrine (i.e., adrenaline); levonordefrin (i.e.,nordefrin); and glutamate receptor inhibitors; or pharmaceuticallyacceptable salts thereof. In some embodiments, the vasoconstrictor isoxymetazoline, or a pharmaceutically acceptable salt thereof. In otherembodiments, the oxymetazoline is an oxymetazoline HCl salt.

In some embodiments, the pharmaceutical composition comprises about0.01-1.0% (w/v) oxymetazoline HCl. In other embodiments, thepharmaceutical composition comprises about 0.05% (w/v) oxymetazoline.

In some embodiments, the pharmaceutical composition (including theintranasal pharmaceutical composition) further comprises a preservative.In some embodiments, the preservative includes, but is not limited to,sugar alcohols (e.g., sorbitol and mannitol), ethanol, benzyl alcohol,isopropanol, cresol, chlorocresol, and phenol. In some embodiments, thepreservative is benzyl alcohol. In some embodiments, the intranasalpharmaceutical composition comprises about 0.5-2.0% (w/v) benzylalcohol. In other embodiments, the pharmaceutical composition comprisesabout 0.9% (w/v) benzyl alcohol.

In some embodiments, the pharmaceutical composition (including theintranasal pharmaceutical composition) further comprises a viscosityenhancing agent. In some embodiments, the viscosity enhancing agentincludes, but is not limited to methylcellulose, hydroxyethyl cellulose,hydroxypropylmethylcellulose and smart hydrogel. In some embodiments,the viscosity enhancing agent is hydroxyethylcellulose. In someembodiments, the intranasal pharmaceutical composition comprises about0.01-1.0% (w/v) hydroxyethylcellulose. In other embodiments, theintranasal pharmaceutical composition comprises about 0.05% (w/v)hydroxyethylcellulose.

In some embodiments, the pharmaceutical composition is formulated as agel or a liquid. In some embodiments the liquid is water, a sugaralcohol, an alcohol (e.g., ethanol), or any other anesthetic solventthat is biologically compatible with the target tissue.

In some embodiments, the pH of the pharmaceutical composition is betweenabout 4.0 to about 7.5. In other embodiments, the pH of thepharmaceutical composition is between about 4.0 to about 6.5. In anotherembodiment the pharmaceutical composition has a pH of about 5.5 to about6.5. In further embodiments, the pharmaceutical composition has a pH ofabout 6.0 to about 6.5.

In a particular embodiment, the pharmaceutical composition comprisestetracaine, oxymetazoline and benzyl alcohol. In another embodiment, thepharmaceutical composition comprises tetracaine HCl, oxymetazoline HCl,anhydrous citric acid (for pH control), sodium hydroxide (for pHadjustment), benzyl alcohol, hydrochloric acid (for pH control),hydroxyethylcellulose, and purified water. In a more particularembodiment, the pharmaceutical composition of the present inventioncomprises the components, and respective amounts, listed in Table 1below (referred to herein as the “Table 1 formulation”). In a furtherembodiment, the Table 1 formulation is for intranasal administration.

TABLE 1 Ingredient Formulation (% w/v) Tetracaine hydrochloride, USP3.00 Oxymetazoline hydrochloride, USP 0.05 Citric acid anhydrous, USP1.00 Sodium hydroxide, NF q.s. Benzyl alcohol, NF 0.90 Hydrochloricacid, NF q.s. Hydroxyethylcellulose, NF (5000 cps) 0.05 Purified water,USP q.s. to 100%

In another aspect, the present invention provides a method ofanesthetizing at least a portion of a body part, organ, or tissue byadministering a pharmaceutical composition of the invention. In someembodiments, such a pharmaceutical composition is administeredtopically. In some embodiments, the tissue is epithelial tissue. Inother embodiments, the tissue is mucosal tissue. In yet otherembodiments, the mucosal tissue is a tissue or membrane present in theear, throat, mouth (e.g., gums), eye, nose, rectal area and/or theurogenital tract (such as the vagina).

In another aspect, the invention provides a method for anesthetizing atleast a portion of a patient's maxillary dental arch (and pain fibersexternal to the dental arch) in a subject comprising selectivelydelivering into the nasal cavity of the subject a pharmaceuticalcomposition of the invention, wherein at least a portion of thepharmaceutical composition is absorbed by nasal tissue located at therear of the nasal cavity in the vicinity of the sphenopalatine ganglionand, consequently, the maxillary nerve (and/or structures thatcommunicate with the maxillary nerve), thereby anesthetizing at least aportion of the maxillary dental arch (and pain fibers outside, butaround the maxillary arch) of the subject of the subject. In someembodiments, the pharmaceutical compositions is delivered into the nasalsinus and/or rear of the nasal cavity of the subject. In someembodiments, the tissues around the maxilla are also anesthetized. Insome embodiments, the pharmaceutical composition is delivered bynebulization, ionophoresis, laser, ultrasound (typically at greater than20,000 cycles/second) or spraying. In some embodiments thepharmaceutical composition and/or target tissue are chilled or heatedbefore administration. In some embodiments, the pharmaceuticalcomposition is delivered by spraying. In other embodiments, thedelivered spray is a stream or a plume.

In some embodiments, the method comprises spraying the intranasalpharmaceutical composition of the invention 1-5 times into each of thenostrils of the subject. In other embodiments, the method comprisesspraying the pharmaceutical composition of the invention 3 times intoeach of the nostrils of the subject. In some embodiments, each of thesprays are administered within about 1-10 minutes, of each other. Forexample, spray #1 may be administered, followed by an interval of about1-10 minutes, after which spray #2 is administered, followed by aninterval of about 1-10 minutes after which spray #3 is administered,etc. In some embodiments, the interval between sprays is about 1-6minutes. In some embodiments, the interval between sprays is about 2-6minutes. In other embodiments, the interval between sprays is about 3-5minutes. In yet other embodiments, the interval between sprays is about4 minutes.

In some embodiments, the method comprises delivering a known (e.g.,metered) amount of tetracaine into the nasal cavity of the subject. Insome embodiments, the method comprises delivering about 12-50 mg oftetracaine into the nasal sinuses and/or rear of the nasal cavity of thesubject. In other embodiments, the method comprises delivering about15-24 mg of tetracaine into the nasal sinuses and/or rear of the nasalcavity of the subject. In another embodiment, the method comprisesdelivering about 15-20 mg of tetracaine into the nasal sinuses and/orrear of the nasal cavity of the subject.

In some embodiments, the particle size of the pharmaceutical compositiondelivered to the rear of the nasal sinuses and/or rear of the nasalcavity is about 5-50 microns (μm). In other embodiments, the particlesize of the pharmaceutical composition is about 10-20 microns. In otherembodiments, the pharmaceutical composition is delivered in a mannersuch that at least 85% of the particles are at least about 10 microns orlarger. In yet other embodiments, the particle size of thepharmaceutical composition is about 10 microns or larger.

In another aspect, the invention provides a spray device for intranasaldelivery of a pharmaceutical composition of the present invention. Insome embodiments, the spray device is capable of delivering theintranasal pharmaceutical composition to the nasal tissue located at therear of the nasal cavity. In other embodiments, the spray device iscapable of delivering the intranasal pharmaceutical composition to thenasal tissue located in the nasal sinuses and at the rear of the nasalcavity, in the vicinity of the maxillary nerve and/or structures thatcommunicate with the maxillary nerve. In yet other embodiments, thespray device is pre-filled with an intranasal pharmaceutical compositionof the present invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a cross-sectional side view of a person's nasal cavity,maxillary dentition and associated nerves. Both the greater and lesserpalatine nerves originate at the pterygopalatine (sphenopalatine)ganglion. The anterior, middle and posterior superior alveolar nervesoriginate at the maxillary nerve. The nasopalatine branch of theanterior superior alveolar nerve communicates between the alveolarnerves and the palatine nerves. The nerve endings of the anteriorsuperior alveolar nerve are located in the front teeth. The nerveendings of the middle superior alveolar nerve are located in the middleteeth (i.e., the first molars and upper first and second bicuspids onboth sides of the maxillary arch). The nerve endings of the posteriorsuperior alveolar nerve are located in the rear teeth (i.e., the distalone half of the upper first molars and second and third molars). Thesenerves and the preceding nerves (which are joined at the maxillarynerve) are primarily responsible for the transmission of pain impulsesfrom the teeth to the brain. The greater palatine nerve, whose nerveendings are in the hard, is responsible (along with the precedingnerves) for the transmission of pain impulses from the hard palate tothe brain. Similarly, the lesser palatine nerve, whose nerve endings arein the soft palate, is responsible (along with the preceding nerves) forthe transmission of pain impulses from the soft palate to the brain.

FIG. 2 compares methods of delivering local anesthetics by needleinjection with a method of delivering an intranasal pharmaceuticalcomposition of the present invention.

FIG. 3 illustrates the spray angles of the tip of the spray device (withrespect to the horizontal plane) during administration of a nasalformulation.

DETAILED DESCRIPTION OF THE INVENTION

In order that the invention herein described may be fully understood,the following detailed description is set forth.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as those commonly understood by one of ordinaryskill in the art to which this invention belongs. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, suitable methods andmaterials are described below. The materials, methods and examples areillustrative only, and are not intended to be limiting. Allpublications, patents and other documents mentioned herein areincorporated by reference in their entirety.

Throughout this specification, the word “comprise” or variations such as“comprises” or “comprising” will be understood to imply the inclusion ofa stated integer or groups of integers but not the exclusion of anyother integer or group of integers.

In order to further define the invention, the following terms anddefinitions are provided herein.

Definitions

“Anesthetizing” as used herein refers to administering an anestheticcompound (e.g., tetracaine) for the purpose of preventing sensationand/or reducing pain.

“Intranasal formulation” as used herein refers to a formulation that isdelivered to the nasal cavity and/or nasal sinuses.

“Local anesthetic” as used herein refers to an anesthetic delivered nearthe nerve ending to be anesthetized which diffuses after introductioninside the tissue. A local anesthetic is capable of penetrating thetissue deep enough so as to reach the target nerves and nerve branches.A local anesthetic is different from a “topical anesthetic” in that atopical anesthetic only provides surface anesthesia to a depth ofapproximately 1-2 mm. A topical anesthetic does not penetrate deepenough in the tissue to reach nerve branches or teeth.

“Maxilla” as used herein refers to either of a pair of bones of thehuman skull fused to form the upper jaw. The maxilla is sometimes simplyreferred to as the upper jaw.

“Maxillary dental arch” or “maxillary arch” as used herein refers to thecurved structure formed by the maxillary (upper) teeth in their naturalposition.

“Mucosal tissue” or “mucous tissue” as used herein refers to a type ofepithelial tissue. Mucosal tissue refers to the layer of tissue whichcovers the surface of organs or lines a cavity. Non-limiting examples ofmucosal tissue include, tissue in the ear, throat, mouth, eye, nose,rectal area and/or the urogenital tract (such as the vagina).

“Pulpal anesthesia” as used herein refers to a level of anesthesia suchthat when a electric pulp testing (EPT) stimulation (i.e., a reading of65 on the pulp tester) is administered to a tooth, the subject indicatesno pain sensation in the tooth.

“Preceding nerves” as used herein refers to nerve endings and nerveslocated upstream, usually present in a more central neural bundle, froma particular reference nerve.

“Subject” as used herein refers to an animal including a mammal (e.g., ahuman).

“Tetracaine” (sometimes referred to as “amethocaine”) as used hereinrefers to (2-(dimethylamino)ethyl 4-(butylamino)benzoate) and any saltthereof. Tetracaine HCl refers to the HCl salt of 2-(dimethylamino)ethyl4-(butylamino)benzoate.

Pharmaceutical Compositions

The present invention provides tetracaine based anesthetic formulations.These formulations are useful for anesthetizing at least a portion of abody part, organ, or tissue. In one aspect, the present inventionprovides a pharmaceutical composition for anesthetizing at least aportion of a body part, organ, or tissue by administering apharmaceutical composition of the invention. In some embodiments, thepharmaceutical composition described herein is delivered directly to thetarget body part, organ, or tissue.

In some embodiments, the target tissue is epithelial tissue. In otherembodiments, the target tissue is mucosal tissue. In yet otherembodiments, the mucosal tissue is a tissue or membrane present in theear, throat, mouth (e.g., gums), eye, nose, rectal area and/or theurogenital tract (such as the vagina).

In some embodiments, the present invention provides intranasalformulations of tetracaine. Such formulations are useful foranesthetizing the maxillary dental arch and pain fibers around themaxillary dental arch. Such formulations are useful as localanesthetics.

Tetracaine is unique in that it is both stable and highly protein boundcompared to nearly all other local anesthetics. Because of itsprotein-bound nature and smaller molecular weight, tetracaine is betterable to penetrate and adhere to the protein-covered membranes of nervecells and is better able to penetrate the nerve so as to induce ananesthetic effect (especially when present in a formulation containingat least some of, e.g., vasoconstrictors, surfactants, emulsifiers,solvents, pH modifiers and preservatives) when compared to otherester-based anesthetics such as cocaine, procaine, chloroprocaine andbenzocaine. In addition, other ester-based local anesthetics are verytoxic in small amounts and have also been shown to be unstable.Amide-based local anesthetics such as lidocaine, mepivacaine,bupivacaine, etidocaine, prilocaine, and ropivacaine, while proteinbound, are not as effective as tetracaine (especially when tetracaine ispart of one of the formulations of the present invention).

As such, the present invention provides a pharmaceutical compositionsuitable for administration of tetracaine or a pharmaceuticallyacceptable salt thereof. In certain embodiments, the pharmaceuticalcomposition comprises a) tetracaine, or a pharmaceutically acceptablesalt thereof; b) a vasoconstrictor; and c) a pharmaceutically acceptablecarrier. In other embodiments, the pharmaceutical composition comprisesa) tetracaine, or a pharmaceutically acceptable salt thereof; b) avasoconstrictor; c) a preservative; d) a viscosity enhancing agent; ande) a pharmaceutically acceptable carrier. In some embodiments, thecomposition comprises about 2.0-5.0% (w/v) tetracaine. In someembodiments, the composition comprises about 2.25-4.75% (w/v)tetracaine. In other embodiments, the composition comprises about2.5-4.0% (w/v) tetracaine. In yet other embodiments, the pharmaceuticalcomposition comprises about 2.5-3.5% (w/v) tetracaine. In a particularembodiment, the pharmaceutical composition comprises about 3% (w/v)tetracaine. In some embodiments, the pharmaceutical composition is forintranasal administration.

Any vasoconstrictor may be used in the pharmaceutical composition ofthis invention. The vasoconstrictors used in the pharmaceuticalcompositions of the invention has several purposes. First, thevasoconstrictor shrinks the tissue (e.g., nasal tissue) therebyenhancing penetration of the anesthetic into the tissue (e.g., deeperinto the nasal cavity). Second, once the vasoconstrictor has beenabsorbed into the desired area, it inhibits systemic migration of theanesthetic, thereby allowing the anesthetic to remain at a desired site.Third, the vasoconstrictor reduces blood flow to the desired tissue,thereby increasing the duration of the anesthetic's effectiveness(typically by activating G-protein coupled receptors which rendermetallic ionophores in the nerve membrane more sensitive to thetetracaine base). Typical vasoconstrictors useful in the pharmaceuticalcompositions of this invention include but are not limited to indirectα₁-adrenergic agonists such as phenylephrine; calcium channel blockers;meperidine; imidazole drugs such as oxymetazoline and xylometazoline;α₂-adrenergic agonists such as guanfacine; imidazoline (I₁) ligands;direct α₂-adrenergic agonists such as clonidine; substance Pblockers/reducers such as capsaicin; I-menthol; icilin; and glutamatereceptor inhibitors; or pharmaceutically acceptable salts thereof. Insome embodiments, the vasoconstrictor includes but is not limited tooxymetazoline, xylometazoline, guafacine, clonidine, phenylephrine,meperidine, capsaicin; I-menthol; icilin and pharmaceutically acceptablesalts thereof. In some embodiments, the vasoconstrictor isoxymetazoline, or a pharmaceutically acceptable salt thereof. In otherembodiments, the oxymetazoline is an oxymetazoline HCl salt.

The concentration of vasoconstrictor used in the pharmaceuticalcomposition of the instant invention will depend on the specificvasoconstrictor and the desired vasoconstricting effect. Typical rangesof concentrations include but are not limited to about 0.01-5% (w/v). Insome embodiments, the composition comprises about 0.01-1.0% (w/v) (e.g.,oxymetazoline HCl salt). In yet other embodiments, the compositioncomprises about 0.05% (w/v) (e.g., oxymetazoline HCl salt).

In addition to its vasoconstricting activity, oxymetazoline has beenshown to have a degree of anesthetic affect. Oxymetazoline affectsG-protein coupled receptors and, in turn, K⁺, Na⁺, and Ca⁺ channelspresent in nerve cells. In particular, oxymetazoline enhances K⁺, Na⁺,and Ca⁺ permeability such that the nerve is no longer polarized and,thus, is unable to fire and transmit pain impulses.

In some embodiments, the pharmaceutical composition of this inventionfurther comprises a preservative. Examples of preservatives include, butare not limited to sugar alcohols (e.g., sorbitol and mannitol),ethanol, benzyl alcohol, isopropanol, cresol, chlorocresol, phenol andbenzalkonium chloride (BAK). In some embodiments, the preservative isbenzyl alcohol. Benzyl alcohol is particularly desirable because itexhibits an anesthetic effect and works to enhance the effect oftetracaine in a synergistic manner.

The concentration of preservative used in the pharmaceutical compositionof the instant invention will depend on the specific preservative.Typical ranges of concentrations of preservatives are about 0.1-5%(w/v). In some embodiments, the composition comprises about 0.5-2.0%(w/v). In other embodiments, the composition comprises about 0.9% (w/v)(e.g., benzyl alcohol).

The anesthetic, vasoconstrictor and other agents used in thecompositions of the present invention may be dispersed in an appropriatecarrier in order to control the dosage, absorption rate and otherdesired properties. Pharmaceutically acceptable carriers useful in thepresent invention include but are not limited to aqueous carriers, gelcarriers, emulsifiers, surfactants, time release vehicles,nanoparticles, microspheres, intra- and para-cellular transportchemicals, polymers, and chitin. Examples of aqueous carriers include,but are not limited to, water, buffers (e.g., phosphate buffer, citratebuffer), sugar alcohols, alcohols such as ethanol, or any other solventthat is biologically compatible with the target tissue.

Saline is not an appropriate carrier for use with the compositions ofthe present invention. Specifically, it has been discovered that thecompositions of the present invention are unstable in saline asexhibited by the formation of a precipitate.

The pH of the pharmaceutical composition of the present invention istypically adjusted to be compatible with the pH of the tissue to whichit is being administered (e.g., the nasal cavity). Typically, thecomposition has a pH of about 4.0-6.5. In some embodiments, thecomposition has a pH of about 5.5-6.5. In further embodiments, thepharmaceutical composition has a pH of about 6.0 to about 6.5. Theskilled artisan will appreciate that higher or lower pHs than thoserecited may be required and would readily know how to adjust the pHaccordingly.

In some embodiments, the pharmaceutical composition of this inventionfurther comprises a viscosity enhancing agent. Examples of viscosityenhancing agents include, but are not limited to methylcellulose,hydroxyethylcellulose, hydroxypropylmethylcellulose and smart hydrogel.In some embodiments, the viscosity enhancing agent ishydroxyethylcellulose.

Viscosity enhancing agents aid in controlling the mobility of theformulation before, during, and after application of the formulation toa target body part, tissue or organ. For example, viscosity enhancingagents aid in controlling the amount of formulation that either dripsout of the nostrils or into the throat of the subject by reducing themobility of the applied formulation. Viscosity enhancing agents alsoincrease the amount of time the formulation is in contact with thevasculature (e.g., nasal vasculature) which helps to increase the uptakeefficiency of the formulation to the vasculature. In addition, viscosityenhancing agents further dilute moieties present in the nasal passagethat degrade esters (e.g., esterase) and can be mildly cilio-inhibitory.

The concentration of viscosity enhancing agent used in thepharmaceutical composition of the instant invention will depend on thespecific viscosity enhancing agent. Typical ranges of viscosityenhancing agents, include 0.01 to 5% (w/v). In some embodiments, thepharmaceutical composition comprises about 0.01-1.0% (w/v). In otherembodiments, the composition comprises about 0.05% (w/v) (e.g.,hydroxyethylcellulose). The inventors have observed that compositionscomprising high amounts of viscosity enhancing agents (e.g.,hydroxyethylcellulose) result in clogging of the spray apparatus (e.g.,the BD Accuspray™ device).

In one embodiment, the pharmaceutical composition of the presentinvention comprises the following components: tetracaine HCl,oxymetazoline HCl, anhydrous citric acid (for pH control), sodiumhydroxide (for pH adjustment), benzyl alcohol, hydrochloric acid (for pHcontrol), hydroxyethylcellulose, and purified water. In a particularembodiment, the pharmaceutical composition is for intranasaladministration.

In a particular embodiment, the pharmaceutical composition of thepresent invention is the Table 1 formulation. In another embodiment, theTable 1 formulation is for intranasal administration.

In one embodiment, the Table 1 formulation has a pH of between about4.0-6.5. In another embodiment the Table 1 formulation has a pH ofbetween about 5.5-6.5. In another embodiment the Table 1 formulation hasa pH of about 6.0 to about 6.5.

The pharmaceutical compositions of the present invention may beadministered in several forms. Examples of suitable formulationsinclude, but are not limited to, solutions, sprays, suspensions,lotions, gels, creams, foams, oils, emulsions, ointments, powders (suchas CaCO₃ containing powders), lyophilized powders, or suppositories.

One of skill in the art will appreciate that the type of formulationused will depend on, for example, the amount of active ingredient to beadministered and the target body part, organ or tissue.

Suitable lotion or cream formulations may comprise, for example, mineraloil, dimethyl sulfoxide (DMSO), sorbitan monostearate, polysorbate 60,cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, orcombinations thereof.

Suitable gel formulations may comprise, for example, modified celluloses(e.g., hydroxypropyl cellulose and hydroxyethyl cellulose), carbopolhomopolymers and copolymers, solvents such as diglycol monoethyl ether,alkylene glycols (e.g., propylene glycol), dimethyl isosorbide, alcohols(e.g., isopropyl alcohol and ethanol), isopropyl myristate, ethylacetate, C₁₂-C₁₅ alkyl benzoates, mineral oil, squalane, cyclomethicone,capric/caprylic triglycerides, or combinations thereof.

Suitable foam compositions may comprise, for example, an emulsion and agaseous propellant. Examples of gaseous propellants include, but are notlimited to, hydrofluoroalkanes (HFAs) such as 1,1,1,2-tetrafluoroethane(HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227).

Suitable oil formulations may comprise, for example, natural andsynthetic, oils, fats, fatty acids, lecithins, triglycerides, orcombinations thereof.

Suitable ointment formulations may comprise, for example, hydrocarbonbases (e.g., petrolatum, white petrolatum, yellow ointment, and mineraloil), absorption bases (e.g., hydrophilic petrolatum, anhydrous lanolin,lanolin, and cold cream), water-removable bases (e.g., hydrophilicointment), water-soluble bases (e.g., polyethylene glycol ointments),propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, orcombinations thereof.

In other embodiments, the pharmaceutical compositions optionallycomprise pharmaceutically acceptable excipients. Examples ofpharmaceutically acceptable excipients include, but are not limited to,preservatives, surfactants, stabilizing agents, emulsifiers,antibacterial agents, buffering agents and viscosity modifying agents.Specific examples of such excipients are discussed above.

Examples of emulsifiers include, but are not limited to, acacia, anionicemulsifying wax, calcium stearate, carbomers, cetostearyl alcohol, cetylalcohol, cholesterol, diethanolamine, ethylene glycol palmitostearate,glycerin monostearate, glyceryl monooleate, hydroxpropyl cellulose,hypromellose, lanolin, hydrous, lanolin alcohols, lecithin, medium-chaintriglycerides, methylcellulose, mineral oil and lanolin alcohols,monobasic sodium phosphate, monoethanolamine, nonionic emulsifying wax,oleic acid, poloxamer, poloxamers, polyoxyethylene alkyl ethers,polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fattyacid esters, polyoxyethylene stearates, propylene glycol alginate,self-emulsifying glyceryl monostearate, sodium citrate dehydrate, sodiumlauryl sulfate, sorbitan esters, stearic acid, sunflower oil,tragacanth, triethanolamine and xanthan gum.

Methods of Anesthetizing Tissue

In one aspect, the present invention provides a method of anesthetizingat least a portion of a body part, organ, or tissue by administering apharmaceutical composition of the invention. In some embodiments, thepharmaceutical composition is topically administered to the target bodypart, organ, or tissue. In some embodiments, the pharmaceuticalcomposition is rubbed, sprayed, or spread on to the target body part,organ, or tissue. In some embodiments the pharmaceutical compositionand/or target tissue are chilled before administration. In otherembodiments the pharmaceutical composition and/or target tissue areheated before administration. In other embodiments, the pharmaceuticalcomposition is administered by nebulization or injection. In yet otherembodiments, the pharmaceutical composition is administered vizionophoresis or ultrasound (typically at greater than 20,000cycles/second).

Any delivery device may be used to apply the pharmaceutical compositionto the body part, organ, or tissue. Examples of suitable deliverydevices include, but are not limited to squeeze bottles, syringes,pneumatically pressurized devices, pump sprayers, positive pressurenebulizers and the like. In some embodiments, the device used ispre-filled with a pharmaceutical composition of the present invention.

In some embodiments, the invention provides a method for anesthetizingat least a portion of a patient's maxillary dental arch (and pain fibersexternal to the dental arch) in a subject comprising selectivelydelivering into the nasal cavity of the subject a pharmaceuticalcomposition of the invention, wherein at least a portion of thepharmaceutical composition is absorbed by nasal tissue located at therear of the nasal cavity in the vicinity of the sphenopalatine ganglionand, consequently, the maxillary nerve (and/or structures thatcommunicate with the maxillary nerve), thereby anesthetizing at least aportion of the maxillary dental arch (and pain fibers outside but aroundthe maxillary arch of the subject) of the subject. In some embodiments,the pharmaceutical compositions is delivered into the nasal sinusesand/or rear of the nasal cavity of the subject. In some embodiments, themaxillary dental arch is anesthetized without producing facial numbnessof the eye, surface of the nose, cheeks or lips. In some embodiments,the tissues around the maxilla (e.g., mucosal tissue such as gums) arealso anesthetized. In some embodiments, the pharmaceutical compositionis delivered by nebulization or spraying. In some embodiments, thepharmaceutical composition is delivered to the nasal sinuses such as themaxillary sinus. In other embodiments, the pharmaceutical composition isdelivered to the anterior dental plexus, extensions of the middlesuperior nerve, the posterior superior alveolar nerve, the nociceptorsof the facial and buccal nerve, and/or the sphenopalatine(pterygopalatine) ganglion. In some embodiments, the pharmaceuticalcomposition is also delivered to parts of the trigeminal ganglion. Inother embodiments, the delivered spray is a stream or a plume.

In order to anesthetize the maxillary dental arch, the pharmaceuticalcomposition must be administered to the tissue located at the extremerear upper end of the nasal cavity such that the composition is absorbedin the region of the maxillary nerve and the pterygopalatine ganglion.The maxillary nerve as used herein refers to region of the nasal cavitywhere the posterior, middle and anterior superior alveolar nervescollect. These nerves are responsible for the initial transmission oftransmitting pain, temperature and pressure impulses generated by thenerves of the maxillary dentition and surrounding maxillary bone. Afterthe impulses pass through the maxillary nerve and the main trunk of thetrigeminal nerve, they are transmitted to the brain for processing andrecognition.

Any delivery device may be used in the methods of the present invention.Examples of delivery devices suitable for intranasal administrationinclude, but are not limited to squeeze bottles, syringes, pneumaticallypressurized devices, pump sprayers, positive pressure nebulizers and thelike. In some embodiments, the device used is pre-filled with apharmaceutical composition of the present invention. In anotherembodiment, the device used is a BD Accuspray™ device.

In some embodiments, the method comprises spraying the pharmaceuticalcomposition 1-5 times into each of the nostrils of the subject. In otherembodiments, the method comprises spraying the pharmaceuticalcomposition 3 times into each of the nostrils of the subject.

Without being bound by any particular theory, it is believed that theeach spraying may play a unique role in the onset of the anestheticeffect. For example, in embodiments wherein the pharmaceuticalcomposition is delivered in 3 sprays, it is believed that the firstspray begins to neutralize nasal enzymatic pathways (e.g., esterases,cytochrome P450, aldehyde dehydrogenase), which may breakdown thedelivered pharmaceutical composition. It is also believed that the firstspray begins to paralyze the nasal cilia which may otherwise clear thecomposition to, for example, the pharynx. It is further believed thatthe composition delivered in the second and third sprays bring on theanesthetic effect.

In some embodiments, each of the sprays are administered within about1-10 minutes of each other. For example, spray #1 may be administered,followed by an interval of about 1-10 minutes, after which spray #2 isadministered, followed by an interval of about 1-10 minutes, after whichspray #3 is administered, etc. In some embodiments, the interval betweensprays is about 1-6 minutes. In some embodiments, the interval betweensprays is about 2-6 minutes. In other embodiments, the interval betweensprays is about 3-5 minutes. In yet other embodiments, the intervalbetween sprays is about 4 minutes.

The pharmaceutical compositions of the present invention are deliveredto the maxillary sinus and the anterior dental plexus, as well asextensions of the middle superior alveolar nerve and sphenopalatineganglion. Further, the pharmaceutical compositions of the presentinvention anesthetize at least a portion of the branches of themaxillary nerve and the pterygopalatine ganglion. In some embodiments,the pharmaceutical composition is also delivered to parts of thetrigeminal ganglion (e.g., V2-V3 of the trigeminal ganglion). Dependingon the extent of anesthetization, it is possible to anesthetize part orall of the surrounding tissues of the maxillary arch.

In embodiments where the method comprises spraying the pharmaceuticalcomposition into the subject's nose, it has been found that the angle ofspraying aids in targeting the formulation to the relevant portions ofthe nasal cavity described above. For example, where the pharmaceuticalcomposition is delivered in 3 sprays, the following procedure may beused: For the first spray, the tip of the spray device can be positionedat an angle of about 35 to 45 degrees from the horizontal plane whilethe subject looks straight ahead. For the second spray, the tip of thespray device can be positioned at an angle of about −10 to +5 degreesfrom the horizontal plane while the subject looks straight ahead. Thethird spray can be delivered in the same fashion as the first spray. Insome embodiments, the tip of the spray device can be positioned at anangle of about 42 degrees from the horizontal plane for the first andthird sprays, and can be positioned at an angle of about zero degreesfor the second spray. In other embodiments, the tip of the spray deviceis positioned approximately 0-2 mm inside the nose during sprayings.

In some embodiments, the targeting of specific teeth is desired. Thus,further refinements in the positioning of the spray device, in additionto those described above, may be employed. Without being bound by thefollowing techniques, it is believed that the following modes ofadministration may also be employed. To target the anterior teeth (i.e.,teeth 6-11), the spray device is angled about 0 to 15 degrees toward themidsagittal plane. To target the bicuspids (i.e., teeth 4, 5, 12, and13), the spray device is angled about 5 degrees away to about 5 degreestoward the midsagittal plane. To target the posterior teeth (i.e., themolars or teeth 1-3 and 14-16), the spray device is angled about 0 to 10degrees away from midsagittal plane. In other embodiments, the spraydevice is angled about 5 to 10 degrees toward the midsagittal plane forthe anterior teeth, about parallel to the midsagittal plane for thebicuspids, and about 5 degrees away from midsagittal plane for theposterior teeth.

Tooth targeting may be further refined by varying the depth at which thespray device is placed within the nostril. For example, when spraying,the spray device can be placed about 2-3 mm within the nostril to targetthe anterior teeth, about 5 mm within the nostril to target thebicuspids, and about 7-9 mm to target the posterior teeth.

In some embodiments, a known (e.g., metered) amount of tetracaine isdelivered into the nasal cavity of the subject. In other embodiments,the known (e.g., metered) amount of tetracaine is delivered into thenasal sinuses and/or rear of the nasal cavity of the subject. Typically,the amount of tetracaine delivered to the nasal sinuses and/or rear ofthe nasal cavity of the subject is about 12-50 mg of tetracaine. In someembodiments, about 15-24 mg of tetracaine is delivered into the nasalsinuses and/or rear of the nasal cavity of the subject. In someembodiments, about 15-20 mg of tetracaine is delivered into the nasalsinuses and/or rear of the nasal cavity of the subject. In someembodiments, the composition comprises about 2.0-5.0% (w/v) tetracaine.In some embodiments, the composition comprises about 2.25-4.75% (w/v)tetracaine. In other embodiments, the composition comprises about2.5-4.0% (w/v) tetracaine. In yet other embodiments, a compositioncomprising about 2.5-3.5% (w/v) tetracaine is used. In a particularembodiment, the composition comprises about 3% (w/v) tetracaine. Theinventors have observed that compositions comprising 2% tetracaine donot result in pulpal anesthesia, possibly due to insufficient amounts oftetracaine. The inventors also observed that compositions comprising 4%or more tetracaine were not as effective in inducing pulpal anesthesia.

In some embodiments, the particle size of the pharmaceutical compositiondelivered to the nasal sinuses and/or rear of the nasal cavity is about5-50 microns. In other embodiments, the particle size of thepharmaceutical composition is about 10-20 microns. In some embodiments,the pharmaceutical composition is delivered in a manner such that atleast 50% of the particles are at least about 10 microns or larger. Inother embodiments, the pharmaceutical composition is delivered in amanner such that at least 65% of the particles are at least about 10microns or larger. In other embodiments, the pharmaceutical compositionis delivered in a manner such that at least 85% of the particles are atleast about 10 microns or larger. In yet other embodiments, thepharmaceutical composition is delivered in a manner such that at least90% of the particles are at least about 10 microns or larger. In furtherembodiments, the pharmaceutical composition is delivered in a mannersuch that at least 95% of the particles are at least about 10 microns orlarger.

These and other embodiments of the invention may be further illustratedin the following non-limiting Examples.

Examples Example 1: Identification of Effective and Safe Dosage ofTetracaine HCl Solution

The purpose of this study was to identify an effective and safe dosageof an intranasally administered tetracaine hydrochloride solution forobtaining anesthesia of the maxillary dentition. Healthy humanvolunteers were administered a dose of tetracaine HCl delivered as anasal spray using a BD Accuspray™ device. The administration of thelocal anesthetic varied by total dose, concentration, and volume, and itincluded single doses in a single nostril, split doses in the samenostril, and divided doses in both nostrils. Different techniquesregarding direction of spray were also investigated.

The efficacy of tetracaine hydrochloride in 80 subjects was measured bymonitoring pain levels via electric pulp testing (EPT). EPT testing wasaccomplished by passing a current through the tooth to be tested whereinthe lowest level of current is a “0” and the highest level of current isan “80.” Subjects are exposed to an increasing amount of current(starting at 0 and ramping up to 80). If any pain was felt by thesubject, the test was stopped and the EPT reading was recorded. Acomposition was considered successful at anesthetizing a tooth when,upon administration, the subject did not report any tooth pain up to areading of 80.

Subjects received tetracaine doses between 4 and 16 mg. Nasaladministration of tetracaine HCl did not result in maxillary archanesthesia, as indicated by an EPT score of 80, in any of the subjectstested.

Example 2: Dose-Ranging Study of Tetracaine Hydrochloride withOxymetazoline Hydrochloride for Anesthetizing Maxillary Teeth

The purpose of this study, was to identify an effective and safe dosageof tetracaine hydrochloride with oxymetazoline HCl when administered bynasal spray for anesthesia of the maxillary teeth. Two formulations wereadministered to human patients using a BD Accuspray™ device—one with 3%tetracaine and 0.05% oxymetazoline; and another with 4% tetracaine and0.05% oxymetazoline.

In all cases, the initial spray of the formulation was administered at aspray device angle of approximately zero degrees from the horizontalplane with the tip placed 0-2 cm inside the nostril with the subjectlooking straight ahead. For doses requiring more than one spray, theexact procedure set forth above was followed except the spray angle waschanged to approximately 42 degrees. The efficacy of the formulation wasmeasured by monitoring pain levels via electric pulp testing (EPT).

Three dosing regimes consisting of varying amounts of tetracaineHCl:oxymetazoline were evaluated: a) 12:0.2; b) 16:0.2; and c) 18:0.3 mgof tetracaine HCl:oxymetazoline HCl. Of the teeth tested, 60% in groupa), 22% in group b), and 73% in group c) obtained pulpal anesthesia(defined as having at least one test with no sensation in the tooth atmaximum EPT stimulation, i.e., a reading of 80 on the pulp tester).Further, 60% of subjects in group c) exhibited profound anesthesia(defined as having pulpal anesthesia beginning within 30 minutes afterdrug administration and continuing for at least 20 minutes in the firsthour of testing on two of the three teeth tested).

Example 3: Packaging of the Table 1 Formulation

Batches of tetracaine HCl plus oxymetazoline HCl nasal spray werepackaged into 0.5 ml BD Accuspray™ syringe systems with a 0.1 ml fill.Microbial Limits Testing (MLT) and chemistry testing were performed onthe packaged syringes. As the formulation is light, and air/oxygensensitive, contact with light and oxygen was minimized. Nitrogen wasused to blanket bulk surface during processing, holding and filling.

Example 4: Evaluation of Particle Size of Table 1 Formulation Deliveredwith BD Accuspray™

The average droplet size of the Table 1 formulation, when dispensed withthe BD Accuspray™ device, was evaluated. Droplet size was evaluated atdistances of 3 cm and 6 cm from the device tip. The data from theseexperiments is summarized below in Table 2. As demonstrated by the data,on average, less than 1% of the droplets dispensed were less than 10microns in diameter.

TABLE 2 Results of Particle Size Testing Distance From Average Percentof Particles <10 μm Device Tip In Diameter* 3 cm 0.97% 6 cm 0.85%*Average of 10 runs

Example 5: Evaluation of Table 1 Formulation for Anesthetizing MaxillaryTeeth in Healthy Subjects

The Table 1 formulation was evaluated to determine if it: a) providedanesthesia of the maxillary teeth sufficient for the performance ofdental procedures, and provided anesthesia of soft tissue; and b) wassafe and tolerable compared to a sham nasal spray of isotonic saline inthe BD Accuspray™ device, an active control injection of 2% lidocainehydrochloride dental local anesthetic infiltration injection, and a shaminjection.

Test Subjects

A total of 45 human subjects (30 receiving the Table 1 formulation, and15 receiving Lidocaine) were enrolled in an active-controlled study. Allsubjects required an operative restorative procedure on a singlemaxillary tooth, other than a maxillary second or third molar, withtreatment time that not expected to exceed 60 minutes.

Procedures

A schedule of the procedures is presented in Table 3.

TABLE 3 Schedule of Procedures 0 min Administer first dose of nasalspray and perform injection (or sham injection), followed by sips ofwater 4 min Administer second dose of nasal spray, followed by sips ofwater 8 min Administer third dose of nasal spray, followed by sips ofwater 15 min Begin dental procedure 20 min* Soft Tissue Assessment, VAS30 min Soft Tissue Assessment 40 min Soft Tissue Assessment 50 min SoftTissue Assessment 60 min** Global VAS, Soft Tissue Assessment 1 hr 20min Soft Tissue Assessment 1 hr 40 min Soft Tissue Assessment 2 hr SoftTissue Assessment *If subject is not sufficiently anesthetized toproceed with the dental procedure at 15 minutes, start at 20 minutes,immediately after Vital Signs and VAS **VAS will be performed at the endof the dental procedure, regardless of the timepoint. Abbreviations: VAS= Visual Analog Scale

Overview of Procedure

Subjects were randomly assigned a treatment group and treatment order.The order of active drug administration (intranasal versus injection)was also random. Assessment of soft tissue anesthesia was made prior todosing, and at 20, 30, 40, 60, 80, 100, and 120 minutes after dosing. At0 min, either a) a single intraoral injection of lidocaine withepinephrine and sham nasal spray of isotonic saline was given; or b) asham injection (depending on randomization group) and administration ofa spray of the Table 1 formulation was administered. Additional doses ofnasal spray were administered at 4 and 8 minutes. Subjects sippedapproximately 2 oz of water following each active or placebo nasal spraydose. The Heft-Parker visual analog scale (VAS) was administered at 15and 20 minutes after start of dosing. Dental treatment commenced 4minutes after the last dose was given. If patients reported pain, thedental treatment did not commence until the 20 minute mark and anadditional VAS test was given. Vital signs (heart rate, blood pressures,pulse oximetry) were taken before dosing, 15 minutes after the start ofdosing, and at 20, 30, 40, 50, 60, and 120 minutes after the start ofdosing. Global efficacy assessments was made at the end of treatment.

Test Product(s), Dose, and Mode of Administration

The Table 1 formulation was delivered in a BD Accuspray® mono-dose nasalspray device with backstop (BD Medical-Pharmaceutical Systems, FranklinLakes, N.J.). Dose delivery was controlled by the solution concentrationand volume contained in each syringe. All units were filled to deliver0.1 mL. A total of six sprays (three in each nostril) of the Table 1formulation were administered, with four minutes between each nasalspray dose. The total dosing period spanned 8 minutes. The total dosageof the Table 1 formulation was 18 mg tetracaine and 0.3 mgoxymetazoline.

The sham nasal spray consisted of isotonic saline solution.

The active control injection consisted of 2% lidocaine HCl andepinephrine (1:100,000) USP (LolliCaine single-use applicators,Centrix). The injection was performed with a 30-gauge short needleinserted submucosally approximating the apex of the tooth to be treated.The dosage of the 2% lidocaine hydrochloride with 1:100,000 epinephrineinjection consisted of one-half cartridge (0.9 mL) delivered over 30seconds for the treatment of anterior or premolar teeth, and onecartridge (1.8 mL) delivered over 60 seconds for the treatment of afirst molar.

The sham injection consisted of a dental syringe and lidocaine withepinephrine cartridge but with the cap left on a 30-gauge short needletip. The needle cap was held against the mucosa in the proper positionfor the injection for 30 seconds for anterior and premolar teeth and 60seconds for molar teeth. No solution was injected.

A small amount of 20% benzocaine gel was used on all subjects to providetopical anesthesia 1 minute before active or sham needle insertions.

The rescue therapy consisted of 4% articaine hydrochloride with1:100,000 epinephrine injection (Septocaine, Septodont).

The Dosing Algorithm consisted of:

-   -   Administration of topical benzocaine gel 1 min before dosing        with sham or active injection    -   Administration dose of injection or initial dose of nasal spray        (T=0 min)    -   If initial dose was nasal spray, at 4 min, administration of a        second dose of nasal spray    -   If initial dose was nasal spray, at 8 min, administration of a        third dose of nasal spray    -   At 15 min, proceeding with dental treatment

Subjects sipped approximately 2 oz of water one minute after each doseof nasal spray (i.e., at approximately 2 and 5 min, and at 10 min). Whensubjects reported pain at the onset of dental treatment, the dentiststopped treatment and waited five minutes (to a total of 20 minutes poststart of dosing). Subjects who continued to report pain at resumption ofdental treatment were considered “treatment failures” and were givenrescue therapy.

Administration of Treatment

For each spray, the subject was sitting up with their chin slightlydown. During each spray, the subject was instructed to hold his/herbreath. After each spray the subject was asked to gently sniff.

For the first spray, the tip of the spray device was positionedapproximately 0-2 cm inside the nose at an angle of 0 degrees from thehorizontal plane; the subject looked straight ahead. For the second andthird sprays, the tip of the spray device was positioned approximately0-2 cm inside the nose at an angle of 42 degrees from the horizontalplane as illustrated in the diagram below; again the subject lookedstraight ahead.

Assessment of Efficacy

In order to assess soft tissue anesthesia, a dental professional used apressure sensitive mechanical probe (i.e., Rotadent®) and tested thefollowing areas for soft tissue anesthesia: distal to the apex of thetooth in the position of the maxillary first premolar at the deepestpoint in the buccal vestibule; apical to the maxillary lateral incisorat the deepest point in the labial vestibule; incisive papilla; and atthe confluence of the alveolar process and hard palate medial to themaxillary second premolar (near the greater palatine foramen). For eachsite tested, the subject was asked if they felt pain. Efficacy of theformulation was determined by the ability to accomplish the dentalprocedure without the need for rescue drug.

Results

Of the 25 patients that received the Table 1 formulation andsuccessfully completed the study, 22 fully completed theprocedures/testing without the need for rescue therapy for a successrate of −88%. Of the 15 patients that received injected lidocaine andsuccessfully completed the study, 14 fully completed theprocedures/testing without the need for rescue therapy for a successrate of −93%. Accordingly, there is no statistical difference betweenthe intranasal Table 1 formulation and the control, locally injectedlidocaine formulation with respect to their ability to anesthetize thetested teeth. Thus, the Table 1 formulation provides an effective meansof anesthetizing teeth without need for painful injection procedures.

Example 6: Evaluation of Effect of Time Between IntranasalAdministration of Table 1 Formulation Sprays

The effect of the interval time between sprays was evaluated. Inparticular, interval times of about 1, 2, 3, 4, and beyond 4 minuteswere evaluated. It was observed that shorter interval times betweenspray administrations (i.e., interval times of about 1, 2, or 3 minutesbetween sprays) resulted in faster onset of the anesthetic affect, but ashorter duration of the anesthetic effect, when compared to an intervaltime of about 4 minutes. It was also observed that waiting more than 4minutes between spray administrations did not affect the time ofanesthetic onset, but resulted in a short duration of anesthetic affect.

What is claimed:
 1. A pharmaceutical composition comprising: a)tetracaine, or a pharmaceutically acceptable salt thereof; b) avasoconstrictor; and c) a pharmaceutically acceptable carrier.
 2. Thepharmaceutical composition according to claim 1, wherein saidpharmaceutical composition is for intranasal administration.
 3. Thepharmaceutical composition according to claim 1, wherein saidcomposition comprises about 2.25-4.75% (w/v) tetracaine or salt thereof.4. The pharmaceutical composition according to claim 3, wherein saidcomposition comprises about 3% (w/v) tetracaine or salt thereof.
 5. Thepharmaceutical composition according to claim 4, wherein saidcomposition comprises about 3% (w/v) tetracaine HCl.
 6. Thepharmaceutical composition according to claim 1, wherein saidvasoconstrictor is selected from the group consisting of: indirectα₁-adrenergic agonists; calcium channel blockers; meperidine; imidazoledrugs; α₂-adrenergic agonists; imidazoline (I₁) ligands; directα₂-adrenergic agonists; substance P blockers/reducers; I-menthol;icilin; glutamate receptor inhibitors; and pharmaceutically acceptablesalts thereof.
 7. The pharmaceutical composition according to claim 6,wherein said vasoconstrictor is oxymetazoline, or a pharmaceuticallyacceptable salt thereof.
 8. The pharmaceutical composition according toclaim 7, wherein said vasoconstrictor is oxymetazoline HCl.
 9. Thepharmaceutical composition according to claim 8, wherein saidcomposition comprises about 0.01-1.0% (w/v) oxymetazoline HCl.
 10. Thepharmaceutical composition according to claim 9, wherein saidcomposition comprises about 0.05% (w/v) oxymetazoline HCl.
 11. Thepharmaceutical composition according to claim 1, wherein saidcomposition further comprises a preservative.
 12. The pharmaceuticalcomposition according to claim 11, wherein said preservative is selectedfrom the group consisting of: sugar alcohols, ethanol, benzyl alcohol,isopropanol, cresol, chlorocresol, and phenol.
 13. The pharmaceuticalcomposition according to claim 12, wherein said preservative is benzylalcohol.
 14. The pharmaceutical composition according to claim 1,wherein said composition further comprises a viscosity enhancing agent.15. The pharmaceutical composition according to claim 14, wherein saidviscosity enhancing agent is selected from the group consisting of:methylcellulose, hydroxyethyl cellulose, hydroxypropylmethylcelluloseand smart hydrogel.
 16. The pharmaceutical composition according toclaim 15, wherein said viscosity enhancing agent ishydroxyethylcellulose.
 17. The pharmaceutical composition according toclaim 1, wherein said pharmaceutically acceptable carrier is water,sugar alcohol, or alcohol.
 18. A method for anesthetizing at least aportion of a body part, organ or tissue by delivering to said body part,organ or tissue respectively a pharmaceutical composition according toclaim
 1. 19. A device for delivery of a pharmaceutical composition,wherein said device comprises a pharmaceutical composition according toclaim 1.